Uracil ureas

ABSTRACT

D R A W I N G ammoni WHEREIN R is selected from the group consisting of lower alkyl having from one to four carbon atoms, allyl, cyclohexyl and 2-methylphenyl. Said compounds are useful central nervous system anti-depressants.     Uracil ureas having the general formula

United States Patent [1 1 Berger et al.

1*Sept. 25, 1973 URACIL UREAS inventors: Arthur Berger, Skokie, lll.;Edeltraut E. Borgaes, Sindelfingen, Germany Appl. No.: 205,329

Related U.S. Application Data Continuation of Ser. No. 849,889, Aug. I3,1969, abandoned.

vs. C]. 260/2564 c, 424/251 Int. Cl C07d 51/38 Field of Search 260/2564C References Cited FOREIGN PATENTS OR APPLICATIONS l,2l9,489

6/1966 Germany Primary Examiner-Alex Mazel Assistant ExaminerR. V. RushAttorney-Walter C. Kehm [5 7] ABSTRACT Uracil ureas having the generalformula wherein R is selected from the group consisting of lower alkylhaving from one to four carbon atoms, ally], cyclohexyl andZ-methylphenyl. Said compounds are useful central nervous systemanti-depressants.

10 Claims, No Drawings formed during the heating period was filtered offafter the reaction mixture had cooled to room temperature. The filtratewas poured into crushed ice and the resulting white precipitatecollected and washed with water. On drying, this solid weighed 114 grams(69 percent of the theoretical) and had a melting point of 109.8C. Onerecrystallization from methanol raised the melting point to l28.lC and asecond crystallization from the same solvent yield high purityl-n-butyl-3-(2,4-diketo- 1.3-dimethyl-l ,2,3,4-tetrahydropyrimidin-6-yl)urea, m.p. l29.lC.

Other examples of the uracil ureas of the present invention weresynthesized according to the procedure of the above examples. Theanalytical data determined for these compounds are set forth in thefollowing table:

g 1 Three animals tested at each dose.

TABLE I.ANALYTICAL DATA ON URACIL UREAS CIZH: N 0:? C-NIICONHR c1r,N\/0H Analysis, percent Calculated Found Melting Empirical R equals point,C. formula C H N C H N 225-7 Callie-N403 45. 28 5. 70 26. 45.63 5.8326.31 1684) CoHuNKh-Hao 44.26 6.60 22.94 44. 55 6.56 22.90 155-601011141040. 50. 41 5.02 23.52 50.85 6.08 23.32 177 C10II16N4O; 40. 006.71 23.32 50.10 6.66 23.37 167-8 C10H16N4O: 40.00 6.71 23.32 50.36 6.8123.34 116 CllIIlBNlOJ 51.06 7.13 22.03 51.83 7.03 21.04 127-001111185140, 51.06 7.13 22.03 51.00 6.88 21.32 107-0 iaHzoNtOa 55.707.10 10.00 55.71 7.12 10.86 246-8 uHluNlO! 58.32 5.50 10.43 58.72 5.7010.50

The desirable central nervous system anti-depressant TABLE IIIproperties of the uracil ureas of this invention are illus- 40 trated bythe activity of these compounds in protecting mice against lethal dosesof pentobarbital sodium (bar- Reference CNS Anti-depressants (mgJltg. inmice) biturate antagonist activity). These illustrative results NameLDMI BAD, are shown in the following Tables [I and Ill 1n which thepicmmgin 91 g 19 compounds of the present invention are compared with gzfif z ig seven reference central nervous system anti- MEGIWDEH 36 24 L5depressants. In this comparlson, which is a modifica- Pemylenetetrazolsold tion of the rocedure re orted b Kimura and Rich- P P Y "METRAZOL"90 39 2.3 ards, Arch. Intern. Pharmacodym, Vol. 110, pp. 29-42Methylphenidate sold under the trademark (1957), the ability of the testcompound to reverse a "RITAUN" 965 inactive at H50 lethal dose ofbarbiturate 1s determmed. The life or Ethamivan sold under death of thetest animals followin administration of a the trademark I h l d f h b ld f EMIVAN" 37 inactive at 10200 et ose o t e 8r lturate an ose ocaffeine citrate S40 inactive at 35-500 the test compound is used as theend point to provide Nikethamide 245 inactive at 150-300 the valuesgiven in the tables as the effective BAD, (median barbiturate antagonistdose). The margin of safety of the test compound is shown by the ratioof the LD (median lethal dose) to the effective barbiturate antagonistdose.

In this procedure, the LD 's and BAD s were determined by subjecting themice to at least three logarithmically graded doses with 10 mice at eachdose level for each compound and calculating according to the procedureof Miller et al., Proc. Soc'y. Exper. Biol. and Med., Vol. 57, p. 261(1944). The lethal dose of the barbiturate which was administered wasthe LB (the dose required to kill at least nine of every 10 mice), or126 mg./kilo of body weight.

From the results shown in the above tables it can be seen that six ofthe compounds of the present invention are more active than the sevenreference compounds. Most importantly, the safety margins of eight ofthe novel compounds of the present invention are better than any of thereference compounds and six have safety margins of 10 or greater than10.

Various modifications, adaptations and further examples of the presentinvention can be devised, after reading the foregoing specification andthe claims appended hereto, by the person skilled in the art withoutdeparting from the spirit and scope of the invention. Thus, it will beapparent that various mutual solvents other than dimethylformamide anddimethylsulfoxide URACIL UREAS This is a continuation of applicationSer. No. 849,889, filed Aug. 13, 1969, now abandoned.

The present invention relates to novel organic uracil ureas. Moreparticularly, this invention relates to ring substituted uracil ureashaving the general formula:

/CH C ll wherein R is selected from the group consisting of lower alkylhaving from one to about four carbon atoms, allyl, cyclohexyl andZ-methylphenyl.

The compounds of the present invention have been found to have potentcentral nervous system antidepressant activity in animals. The abilityof these compounds to revive animals given large doses of barbiturateshas been shown in mice, rabbits and dogs. As such, the compounds of thepresent invention are useful agents for these and other animals asnarcotic, barbiturate and anesthetic antagonists and as psychomotor andrespiratory stimulants. These compounds are new compounds which have notbeen described heretofore in the literature and have unique barbiturateantagonist properties. Certain S-substituted positional isomers of thepresent compounds have been described heretofore as chemicalintermediates for anti-cancer agents by Johnston et al., J. Med. Chem.,Vol. 6, pp. 66981 (1963). However, the 5-substituted uracil ureas werefound to be inactive central nervous system antidepressants.

The synthesis of the novel uracil ureas of the present invention can beeffected by reacting 6-amino- 1,3dimethyluracil with an appropriateisocyanate. This synthesis is facilitated by reaction in the presence ofa mutual solvent such as an amide, for example, dimethylformamide, or asulfoxide, for example, dimethylsulfoxide.

The general reaction can be described by the following equation:

wherein R is as previously defined.

Illustrative of the isocyanates which can be used in the above reactionare the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, allyl,cyclohexyl and 2- methylphenyl isocyanates and the like. The isocyanatereagents are generally available commercially or can be made byconventional procedures, for example, by reaction of an amine andphosgene as described in Organic Syntheses," Coll. Vol. 11, A. H. Blatt,ed., pp.

4535, and C011. Vol. W, N. Rabjohn, ed., pp. 5214, John Wiley & Sons,lnc., New York and London.

The compound 6-amino-1,3-dimethyluracil also is generally availablecommercially or can be made by conventional procedures, for example, byreaction of 1,3-dimethylurea with ethyl cyanoacetate as described byTraube, Arm., Vol. 432, p. 281 (1923).

Although specific methods of preparation of the novel uracil ureas ofthe present invention are described herein, it will be understood thatthese compounds are not limited to these specific methods ofpreparation. For example, an alternative method of preparation consistsof methylating the ring unsubstituted uracil urea. Other methods ofpreparation of these compounds can be devised by those skilled in theart.

The novel compounds of the present invention have been administered bothintravenously (i.v.) and intraperitoneally (i.p.) in suspensions ofpectin and gum acacia solutions and in alcohol-water solutions. Theseroutes of administration as well as the oral route of administration canbe used. Other methods of administration will be apparent to thoseskilled in the art.

Effective barbiturate antagonist dosages can range from about 1 to 1,000mg. per kg. of body weight and can take the form of tablets, powders,capsules, elixirs and the like dosage forms in admixture with commonsolid and liquid diluents, carriers and adjuvants such as, for example,cornstarch, lactose, talc, stearic acid, magnesium stearate, gelatin,acacia and locust bean gums, alcohol, water, vegetable oils and the likematerials. Other effective dosages of the novel compounds can bedetermined by reference to the specific examples set forth hereinafter.It has been unexpectedly found that high dosages of these compounds losetheir toxicity in the presence of the active barbiturates and thusappear to be less toxic in the presence than in the absence ofbarbiturates.

The following examples will further illustrate the present inventionalthough the invention is not limited to these specific examples. Allpercentages and parts herein are on a weight basis unless otherwisespecified.

EXAMPLE l Synthesis of 1-(2,4-Diketo-1,3-Dimethyl-1,2,3,4-Tetrahydropyrimidiri-6-yl)-3-Ethylurea A mixture of 15.5 grams (0.1mole) of 6-amino-1,3- dimethyl uracil and 12 ml. (an excess) of ethylisocyanate in 200 ml. of dimethylformamide was refluxed for about 20hours. The mixture was allowed to cool to room temperature, then pouredinto crushed ice with stirring. The precipitate which formed wascollected on a filter, then recrystallized from methanol. The whiteproduct thus obtained after drying corresponded to l- (2,4-diketo-1,3-dimethyl-1 ,2,3,4-tetrahydropyrimidin- 6-yl)-3-ethylurea as themonohydrate, weight 18.1 grams (74.2 percent of the theoretical) with amelting point of 168169C.

EXAMPLE ll Synthesis of 1-n-Butyl-3-(2,4-Diketo-l,3-Dimethyl-1,2,3,4-Tetrahydropyrimidin-6-yl) Urea A mixture of 101 grams (0.65mole) of 6-amino-l,3- dimethyl uracil, 124 ml. (1.1 moles) of n-butylisocyanate and 800 ml. of dimethylformamide was heated under reflux for3 hours. A white precipitate which vamino-1,3-dimethyluracil isgenerally reacted with about a molar equivalent or an excess of theisocyanate at reflux temperature. An effective barbiturate antagonistdose of the uracil ureas can be formulated in any conventional dosageform for administration, including admixtures with many solid and liquiddiluents, carriers and adjuvants other than those previously described.These dosages can be administered to revive animals given an overdose ofbarbiturates, sedatives and hypnotics such as, for example,pentobarbital sodium, phenobarbital, phenobarbital sodium, chloralhydrate and the like substances.

wherein R is selected from the group consisting of lower alkyl havingfrom one to four carbon atoms, allyl, cyclohexyl and Z-methylphenyl.

2. The uracil urea of claim 1 in which R is methyl. 3. The uracil ureaof claim 1 in which R is ethyl. 4. The uracil urea of claim 1 in which Ris n-propyl. 5. The uracil urea of claim 1 in which R is isopropyl. 6.The uracil urea of claim 1 in which R is n-butyl. 7. The uracil urea ofclaim 1 in which R is isobutyl. 8. The uracil urea of claim 1 in which Ris ally]. 9. The uracil urea of claim 1 in which R is cyclohexyl. 10.The uracil urea of claim 1 in which R is 2- methylphenyl.

* i t i

2. The uracil urea of claim 1 in which R is methyl.
 3. The uracil ureaof claim 1 in which R is ethyl.
 4. The uracil urea of claim 1 in which Ris n-propyl.
 5. The uracil urea of claim 1 in which R is isopropyl. 6.The uracil urea of claim 1 in which R is n-butyl.
 7. The uracil urea ofclaim 1 in which R is isobutyl.
 8. The uracil urea of claim 1 in which Ris allyl.
 9. The uracil urea of claim 1 in which R is cyclohexyl. 10.The uracil urea of claim 1 in which R is 2-methylphenyl.